Protocol Development for a
Clinical Research Study
L.O. Lutherer, MD, PhD
Executive Director, TTUHSC Clinical Research Institute (CRI)
Professor, Departments of Physiology & Internal Medicine
Copyrighted
How is a Clinical Research Study Born?
• A question is asked.
• An hypothesis and an experimental approach are
developed.
• A Protocol is written to describe and define the study.
• The study is approved by the IRB and, in some cases, by
the FDA.
• Potential subjects are identified, recruited, consented
and enrolled.
• The study starts.
What is a Protocol ?
• A protocol defines & describes exactly what will be
done in a study.
• It is critical for all of the Phases of Clinical Research,
including the preclinical studies.
• It is the description of the study design and includes
elements that will demonstrate safety and support
possible efficacy.
• A good protocol is the best protection for subjects.
• The protocol for both an industry-sponsored and an
investigator-initiated study will define what is
expected of your team and the participants.
Why Is a Protocol Necessary?
• A poorly designed study is unlikely to produce meaningful
results and may produce erroneous information.
• Doing a study on humans that is unlikely to produce
meaningful results is considered unethical.
• The Protocol is the basis for a monitor to follow a study,
identify Protocol Deviations and ensure the validity of the
data.
• Protocol Violations are serious, can compromise safety,
invalidate data, and must be reported to the IRB, who can
close the study until violations have been addressed and
steps to avoid recurrence have been approved.
What to Ask Before Writing a
Protocol:
• Enrollment:
– Are there sufficient potential subjects meeting the
inclusion/exclusion criteria to recruit the number needed?
– How many of these will decide not to participate because of
what is asked or are unwilling to participate in any study?
• Staff:
– Will time demands interfere with the conduct of other studies?
• Funding:
– Will all costs be covered?
• Validity:
– Will this study really yield meaningful results?
The Elements of a Protocol?
1. Title
2. List of Principal Investigator, Co-Investigators and staff
3. Hypothesis or possible correlation
4. Background including references supporting the study
5. Specific Aims & Objectives
6. Significance
7. Study Design (Methods & Statistics)
8. Selection & Enrollments of Subjects
9. Risk/Benefit Considerations
10. Confidentiality Considerations
11. References
The Title
• The Title should be succinct and inform the reader of
what is being studied, and, perhaps, the reason.
• Examples would include:
•
– “Examining whether the ACE inhibitor “Y” is as effective but
has fewer side effects than those currently used.”
– “Testing whether oral administration of drug “Y” is as
effective as intravascular administration.”
– “Does combining drugs “A” and “B” produce a better outcome
than using one or the other separately?”
– “Will drug “A”, approved for treatment of disease X, also be
efficacious in the treatment of disease Y?”
– “Is there a relationship between contracting flu and age?”
The Investigators
• The FDA, any industrial sponsor and any IRB will
assess appropriateness of persons involved in the
study by reviewing whether:
– All persons involved in the study are listed.
– The investigators listed have the background and
experience to conduct the study.
– The team members are qualified to perform the duties
assigned.
– All persons involved have received the required training.
– The Principal Investigator will be responsible
• Competency of investigators will be tested in the near
future.
The Hypothesis
• Some studies are hypothesis-driven, while others are
observational/descriptive.
• A hypothesis defines the potential answer to the
question you are asking and the outcome is defined by
acceptance or rejection (yes/no) of the null hypothesis.
• For a hypothesis-driven study, a power analysis is
required to determine the minimum number of subjects
needed to be able to show a significant difference
between groups if a difference exists.
The Background
•
The background describes the rationale for the study.
•
It identifies the gap in knowledge that the study will
attempt to fill.
•
It reviews studies in the literature providing support for
the hypothesis as well as those that argue against it.
•
It reviews studies suggesting a relationship might exist.
•
It reviews studies that support the study design and the
measurement techniques used to assess the outcomes.
Specific Aims
• Specific Aims define the outcomes to be tested.
• The “Aim” is to obtain results supporting the hypothesis
or demonstrating that a relationship exists.
– We hypothesize that treatment “A” is better than treatment “B”
for controlling blood pressure.
– We will describe the relationship, if any, between the number of
patients admitted with CV disease and the age of the patients.
• Aims may be “short-term” or “long-term” and there may
be more than one.
•
• The more specific the aims, the better the study and the
lower the chance for disorganization and problems.
The Objectives
• Objectives describe how the investigators will test the
outcomes.
• There should be at least one specific outcome that can
be measured.
• Examples might be:
– We will measure the height of children in Lubbock between
the ages of 3 and 15 years every six months and plot their
growth curves.
– We will measure plasma levels of free T4 at the same time and
determine the relationship with the height of the subjects.
The Significance
• Why the study is important.
• What gap in knowledge will be filled.
• How the results can contribute to improving the scientific
understanding.
• How the results can improve the quality of clinical care
delivered.
What is in the Study Design?
• The subject characteristics are defined
• Treatments, treatment groups and length of treatment.
• Samples to be taken, measurements to be made, how
and when (remember to have a “window” for sampling
time).
• Analytical techniques to be used.
• Data to be gathered (CRFs = Case Report Forms).
• Analysis of data & statistical methods to be used.
Defining the Subject Selection
• The population:
– Equal representation within the limits of the experimental design
(i.e., both males and females).
– Source of patients and recruitment techniques.
– Number, gender and age range of the subjects.
– Appropriate adjustments for special (vulnerable) populations
such as minors, pregnant women, prisoners, etc.
• Inclusion criteria:
– Age, gender, and special defined characteristics such as
diagnosed with a given disease, etc.
• Exclusion criteria:
– Outside the defined inclusion criteria, having a concomitant
disease, taking concomitant medications, etc.
The Consent Form
• Provides full disclosure to the subject about what they will
be asked to do, the time cost, risks, their costs, possible
compensation and possible value of findings.
• Subject must understand standard of care treatment and
decide if they prefer it to participation in the study?
• Consent form must use eighth-grade language.
• Must determine that the subject understands everything
in the consent form before they sign.
• Most suits related to research studies are based on, “They
never told me, or I didn’t understand…”
Questions About the Study Design
During the Protocol Review Process.
• Was there early input by a biostatistician?
• Are questions asked consistent with the Aims?
• Are treatment arms appropriate and is there a proper control group?
Are the groups equivalent?
• Will subjects be randomized to avoid bias, and how will it be done?
• Is the study un-blinded, single-blinded or double-blinded?
• Are the statistics correct for analyzing the data?
• How are risks minimized and confidentiality protected?
• Is there sufficient justification?
• Will the results be meaningful?
What Can Result from a Bad Design?
• A poor design might increase the risk and result in
serious adverse events.
• Important data might not be obtained.
• Analysis compromised by an inappropriate statistical
design.
• Inadequate/improper controls will invalidate conclusions.
• Improper inclusion and exclusion criteria will impair
recruiting and may invalidate the data.
• Use of human subjects will have served no purpose.
Amendments to Change the Protocol
• Legitimate reasons exist for changes in the protocol,
often based on unexpected findings.
• Requesting changes should not substitute for faulty
planning.
• Changes are done by through amendments to the IRB
that describe and justify the basis for the changes.
• Amendment must be approved by the IRB and possibly
by the FDA before the changes can be made.
• All amendments must be consistent with original aims.
Risk/Benefit Considerations
• All studies contain some form of risk, even if it is only related to
travel to and from the clinic or loss of confidentiality.
• If the risk/benefit ratio is high, surveillance must also be high.
• A low-risk study is one which poses no greater threat than the
“minimal risk” encountered in normal daily life.
• Potential benefits are usually for the population as a whole and not
for the individual subject.
• Assignment of the ratio can be difficult. Consider the fact that the
chance of being on a plane that crashes is slight, but, if it does
crash, the risk is extreme because death is likely - What level of
risk do you assign here?
References
•
References identify the papers cited in the protocol that
provide supporting evidence for the study, for treatment
methods to be used and for measurements to made.
•
Recent as well as classic publications should be included.
•
References are provided so that a reviewer can
substantiate all statements that are made.
Conclusions
• Research using human subjects is important for improving
the practice and delivery of healthcare.
• Protocol development must be done carefully and
accurately in order to obtain valid results.
•
• A poorly designed study can produce invalid conclusions
and places subjects at risk for no reason.
• The Principal Investigator has the major responsibility for
adherence to the regulations and following the protocol,
but all those on the team are fully accountable.
Questions?